Background: Patients with high-risk features who experience biochemical relapse (BCR) after radical prostatectomy (RP) benefit from the addition of androgen deprivation therapy (ADT) to salvage radiotherapy (SRT). We hypothesized that intensification of androgen receptor (AR) blockade with enzalutamide would improve SRT outcomes for high-risk patients. Methods: Post prostatectomy prostate cancer patients who have had BCR (PSA ≥ 0.2 ng/mL) with at least 1 high-risk feature (Gleason 8-10, seminal vesicle invasion, pN1, persistent PSA >0.1 ng/mL after RP, and PSA ≥ 0.7 ng/mL) were eligible. Patients were randomized 1:1 to 24 months of ADT with an LHRH analog (LHRHa) or intensified ADT comprised of LHRHa + enzalutamide. The primary endpoint was progression free survival (PFS) with progression defined as PSA ≥ 0.05 ng/mL or initiation of new therapy following SRT. The target accrual of 170 patients provided 80% power to detect a HR=0.65 using a one-sided logrank test with a type I error of 0.10. Results: Between April 2019 and August 2022, 188 patients were enrolled. The patient characteristics were well balanced between the two arms. Median age was 64 years. Nodal involvement (pN1), pT3a-b, and Gleason 9 were noted in 22%, 77%, and 52% of patients, respectively. Over 70% had > 1 aggressive feature. Median follow-up time at the time of this report was 15.8 months. Prostatic fossa and pelvic SRT were mandatory. Para-aortic radiotherapy (RT), and lymph node and prostatic fossa lesion RT boosts were left at the discretion of the radiation oncologist. PFS favored the enzalutamide-intensified arm (HR=0.72, 80% confidence interval [CI]:0.56-0.94, one-sided p=0.14). Grade 3 adverse events (AEs) related to treatment in the standard versus enzalutamide arms were 11 vs. 23%, while Grade 4 AEs were 4% vs. 1%, respectively. The most common AEs (all grades, >15%) included hot flashes, fatigue, diarrhea, and decreased lymphocytes. The grade 3+ AEs (>3%) included decreased lymphocytes and hypertension. The largest differences (>7%) in AEs included insomnia, decreased lymphocytes. Diarrhea was less frequent with enzalutamide (40% vs 54%). Conclusions: The addition of enzalutamide to standard ADT did not meaningfully increase toxicity. While there was a trend toward PFS benefit from intensification, it has not yet met statistical significance. Updates on PFS and other clinical endpoints including quality of life will be reported with longer follow-up. Clinical trial information: NCT03809000.